Tetrahydrocarbazole 1-alkanoic acids and pharmaecutical compositions
RELATED CASES 
     This is a division of Ser. No. 076,424, Jul. 21, 1987, U.S. Pat. No. 4,808,608, which is a continuation-in-part of Ser. No. 001,739, Jan. 9, 1987, abandoned, which is a continuation-in-part of Ser. No. 821,726, Jan. 23, 1986, abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to prostaglandin antagonists useful in treating a variety of conditions, such as allergic asthma where excessive contractile activity of prostaglandins and prostaglandin biosynthetic intermediates occur. 
     These compounds antagonize the actions of contractile prostaglandins, such as PGF 2 α, PGG 2 , PGH 2 , PGD 2  and TXA 2 . The use of agents which act as prostaglandin antagonists offers new approaches to therapy in a number of disease states. For example, certain prostaglandins, such as PGF 2 α, PGD 2 , PGG 2 , and PGH 2 , are potent bronchospastic agents. Indeed human asthmatics have been shown to be especially sensitive to the bronchial constricting action of PGF 2 α. 
     DESCRIPTION OF THE INVENTION 
     The present invention relates to novel comPounds of Formula I: ##STR1## wherein: 
     R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently selected from: 
     (1) hydrogen; 
     (2) alkyl having 1 to 6 carbon atoms; 
     (3) alkenyl having 2 to 6 carbon atoms; 
     (4) --(CH 2 ) n  M 
     wherein n is 0 to 3 and M is 
     a) OR 13  ; 
     b) halogen; 
     c) CF 3  ; 
     d) SR 13  ; 
     e) phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of 
     f) COOR 14  ; 
     g) ##STR2## h) tetrazole; i) ##STR3##  wherein R 16  is C 1  to C 6  alkyl, benzyl or phenyl; j) --NR 14  R 14  ; 
     k) --NHSO 2  R 17  wherein R 17  is C 1  to C 6  alkyl, 4-methylphenyl, phenyl, or CF 3  ; 
     l) ##STR4## m) --SOR 13  ; n) --CONR 14  R 14  ; 
     o) --SO 2  NR 14  R 14  ; 
     p) --SO 2  R 13  ; 
     q) NO 2  ; 
     r) ##STR5## s) ##STR6## t) ##STR7## v) N 3  ; u) CN; 
     R 7  is H or alkyl of 1 to 6 carbons; 
     R 8  is H or alkyl of 1 to 6 carbon atoms; 
     each R 9  is independently H, OH, C 1  to C 4  -0-alkyl or alkyl of 1 to 4 carbons; 
     R 10  is COOH; CH 2  OH; CHO; tetrazole; NHSO 2  R 11  wherein R 11  is OH, alkyl or alkoxy of 1 to 6 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbons, halogen, hydroxy, COOH, CN, formyl or to 1 to 6 carbons; CONHSO 2  R 11  ; hydroxymethylketone; CN; or CON(R 9 ) ; 
     r is 1 to 6; 
     each R 13  independently is H; C 1  to C 6  alkyl; benzyl; phenyl or substituted phenyl wherein the substituents are C 1  to C 3  alkyl, halogen, CN, CF 3 , COOR 14 , CH 2  COOR 14 , C 1  to C 3  alkoxy, or C 1  to C 4  perfluoroalkyl; 
     each R 14  is independently H, phenyl, benzyl or C 1  to C 6  alkyl; and, 
     each R 15  independently is H, (CH 2 ) m  COOR 14  wherein m is 0 to 4, C 1  to C 6  alkyl, CF 3 , phenyl, or substituted phenyl wherein substituted phenyl is as defined above in the definition of R 13  ; 
     or a pharmaceutically acceptable salt thereof. 
    
    
     Preferred compounds of the present invention comprise the compounds of formula I wherein: 
     R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently selected from: 
     (1) hydrogen; 
     (2) alkyl having 1 to 6 carbon atoms; 
     (3) alkenyl having 2 to 6 carbon atoms; 
     (4) --(CH 2 ) n  M 
     wherein n is 0 or 1 and M is as defined previously for Formula I; 
     R 10  is COOH; CH 2  OH; CHO; tetrazole; CONHSO s  R 11  wherein R 11  is OH, alkyl or alkoxy of 1 to 6 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbons, halogen, hydroxy, COOH, CN, formyl or acyl to 1 to 6 carbons; hydroxymethylketone; CN; or CON(R 9 ) ; 
     r is 1 to 6; and the remaining substituents are as defined previously for Formula I. 
     More preferred compounds of the present invention comprise the compounds of Formula I. wherein: 
     R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently selected from: 
     (1) hydrogen; 
     (2) alkyl having 1 to 6 carbon atoms; 
     (3) alkenyl having 2 to 6 carbon atoms; 
     (4) M wherein M is as defined initially for Formula I; 
     R 10  is COOH; CH 2  OH; CHO; tetrazole; hydroxymethylketone; 
     r is 1 or 2; and the remaining substituents are as defined initially for Formula I. 
     Most preferred compounds of the present invention comprise the compounds of Formula I. wherein: 
     R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently selected from: 
     (1) hydrogen; 
     (2) alkyl having 1 to 6 carbon atoms; 
     (3) M wherein M is 
     a) OR 13  ; 
     b) halogen; 
     c) CF 3  ; 
     d) SR 13  ; 
     e) COOR 14  ; 
     f) ##STR8## g) tetrazole; h) --SOR 13  ; 
     i) --CONR 14  R 14  ; 
     j) --SO 2  NR 14  R 14  ; 
     k) --SO 2  R 13  ; 
     l) ##STR9## m) CN; n) N 3  ; 
     each R 9  is independently H, or alkyl of 1 to 4 carbons; 
     R 10  is COOH; or tetrazole; 
     r is 1 and the remaining substituents are as defined initially for Formula I. 
     In the above most preferred embodiment, those compounds are particularly preferred wherein at least one of R 1  to R 4  is not hydrogen; one of R 5  or R 6  is not hydrogen; R 7  is hydrogen; R 9  is hydrogen, and the remaining substituents are as defined in the most preferred embodiment.